SARS Coronavirus-2 microneutralisation and commercial serological assays correlated closely for some but not all enzyme immunoassays

Serological testing for SARS-CoV-2-specific antibodies provides important research and diagnostic information relating to COVID-19 prevalence, incidence and host immune response. A greater understanding of the relationship between functionally neutralising antibodies detected using microneutralisation assays and binding antibodies detected using scalable enzyme immunoassays (EIA) is needed in order to address protective immunity post-infection or vaccination, and assess EIA suitability as a surrogate test for screening of convalescent plasma donors. We assessed whether neutralising antibody titres correlated with signal cut-off ratios in five commercially available EIAs, and one in-house assay based on expressed spike protein targets. Sera from recovered patients or convalescent plasma donors who reported laboratory-confirmed SARS-CoV-2 infection (n = 200), and negative control sera collected prior to the COVID-19 pandemic (n = 100), were assessed in parallel. Performance was assessed by calculating EIA sensitivity and specificity with reference to microneutralisation. Neutralising antibodies were detected in 166 (83%) samples. Compared with this, the most sensitive EIAs were the Cobas Elecsys Anti-SARS-CoV-2 (98%) and Vitros Immunodiagnostic Anti-SARS-CoV-2 (100%), which detect total antibody targeting the N and S1 antigens, respectively. The assay with the best quantitative relationship with microneutralisation was the Euroimmun IgG. These results suggest the marker used (total Ab vs. IgG vs. IgA) and the target antigen are important determinants of assay performance. The strong correlation between microneutralisation and some commercially available assays demonstrates their potential for clinical and research use in assessing protection following infection or vaccination, and use as a surrogate test to assess donor suitability for convalescent plasma donation

The impact of eastward enlargement on construction labour markets in EU members states

Describes the impact of eastward enlargement on construction labour markets in EU members states

Low-frequency envelope sensitivity produces asymmetric binaural tuning curves

Neurons in the auditory midbrain are sensitive to differences in the timing of sounds at the two ears—an important sound localization cue. We used broadband noise stimuli to investigate the interaural-delay sensitivity of low-frequency neurons in two midbrain nuclei: the inferior colliculus (IC) and the dorsal nucleus of the lateral lemniscus. Noise-delay functions showed asymmetries not predicted from a linear dependence on interaural correlation: a stretching along the firing-rate dimension (rate asymmetry), and a skewing along the interaural-delay dimension (delay asymmetry). These asymmetries were produced by an envelope-sensitive component to the response that could not entirely be accounted for by monaural or binaural nonlinearities, instead indicating an enhancement of envelope sensitivity at or after the level of the superior olivary complex. In IC, the skew-like asymmetry was consistent with intermediate-type responses produced by the convergence of ipsilateral peak-type inputs and contralateral trough-type inputs. This suggests a stereotyped pattern of input to the IC. In the course of this analysis, we were also able to determine the contribution of time and phase components to neurons' internal delays. These findings have important consequences for the neural representation of interaural timing differences and interaural correlation—cues critical to the perception of acoustic space.16 page(s

A time-series analysis of UK annual and quarterly construction output data (1955-95)

United Kingdom construction output makes a vitally important contribution to the gross domestic product of the UK economy. Nevertheless, despite the obvious importance of UK construction, very little is known about the output behaviour of the industry. This paper endeavours to redress the imbalance by analysing the post-war time-series behaviour of annual and quarterly UK construction output. The primary technique of analysis is to estimate an autoregressive integrated moving-average (ARIMA) model of UK construction output. Such a model proxies the stochastic or random process that underlies UK construction output data. Also, a review is given of the methodology of estimation and diagnostic checking of ARIMA models in the context of UK construction output, together with ex-post and ex-ante forecasts of UK construction output using the estimated ARIMA models.Time-series Data, Arima Models, Random Processes, Ex-post, Ex-ante Forecasts,

The changing role of builders' merchants in the construction supply-chain

Builders' merchants are an integral part of the construction industry, yet rarely are they consulted when discussions take place on the future of the construction industry. Throughout history, builders' merchants have played a dominant role in the construction industry, initially as an intermediary between the artisan and the buyer, and more recently as a source of working capital for contracting firms. The merchanting industry currently is undergoing considerable change. The depressed construction market and the failure of the housing repair and maintenance sector to recover in the first half of the 1990's as activity in the private non-housing repair and maintenance sector has increased, has raised competition between merchants. The major building merchants are becoming larger by acquisition and merger, the smaller merchants are seeking niche areas, and the medium-size firms are under serious threat from acquisition by the larger merchanting firms. The trend towards consolidation in the sector, driven by the need to reduce costs, has meant that the large merchanting firms now control around 60% of the building materials market sales. Factoring is a growing trend, particularly with smaller companies sourcing goods from the cheapest source. The larger merchants have to respond by sourcing goods from the lowest cost base, irrespective of whether they buy from overseas markets. This paper analyses the UK builders merchants sector and evaluates the important role played in the supply chain

Investigating the role of microRNAs in the pathogenesis of cytogenetically normal acute myeloid leukaemia

A previous study published by us identified twelve differentially expressed microRNAs between AML FAB M1 and M5, from these five candidate microRNAs (microRNA-130a, -135b, -146a, -181a and -181b) were selected for further study based on their predicted targeting for inhibition of nine transcription factor mRNAs involved in myeloid differentiation and development (Lutherborrow et al., 2011). In this study through the use of a luciferase reporter assay six of the predicted gene targets (FOS, HOXA10, MAFB, IRF8, KLF4 and MCL-1) identified were as bona fide targets of four of the five candidate microRNAs. The next aim was to assess the effect of over-expressing the microRNAs in AML cell line models (HL-60 and NB4); optimisation of three transfection methods was undertaken. The lipid based transfection reagent lipofectamine 2000 delivered oligonucleotides into HL-60 and NB4 cells at transfection efficiencies of 10% and 40% respectively, but was unable to successfully introduce plasmid to levels required for functional studies. Electroporation was found to be highly variable and toxic resulting in high levels of cell death when introducing oligonucleotides or plasmids. Nucleofection, a more specific method of electroporation, was optimised and was able to successfully transfect a GFP plasmid into the HL-60 cell line at efficiencies of 21-46%, but was unable to transfect oligonucleotides. In preparation for future studies based on the transfection optimisation results, inducible microRNA expression vectors for the candidate microRNAs were successfully cloned. The third part of my work was to examine changes in the candidate microRNA expression levels during normal primary macrophage differentiation to determine if published changes seen in cell line experiments occur in primary cells. Interestingly microRNA-146a was identified as being significantly increased during monocyte to macrophage differentiation in contrast to the published results. Since NF-κβ signalling is known to be important in malignancies, an experiment was performed examining the effect of the candidate microRNAs on NF-κβ signalling using a NF-κβ specific luciferase reporter. Of the candidate microRNAs, only microRNA-146a over-expression resulted in a statistically significantly decreased of luciferase activity (by 60%) and therefore NF-κβ signalling.In summary this work has identified six microRNA:mRNA interactions involved in the myeloid development and it can be hypothesised that these interactions could be involved in the formation of the myeloid differentiation blocks seen in AML. Transfection optimisation has elucidated that stable plasmid over-expression is the best method for microRNA alteration in AML cell lines. Additionally this study has provided a foundation for future projects to further examine the roles of these microRNAs in the pathogenesis of AML

This time it’s different? Effects of the eurovision debate on young citizens and its consequence for EU democracy – evidence from a quasi-experiment in 24 countries

For the very first time in EU history, the 2014 EP elections provided citizens with the opportunity to influence the nomination of the Commission President by casting a vote for the main Europarties’ ‘lead candidates’. By subjecting the position of the Commission President to an open political contest, many experts have formulated the expectation that heightened political competition would strengthen the weak electoral connection between EU citizens and EU legislators, which some consider a root cause for the EU’s lack of public support. In particular, this contest was on display in the so-called ‘Eurovision Debate’, a televised debate between the main contenders for the Commission President broadcasted live across Europe. Drawing on a quasi-experimental study conducted in 24 EU countries, we find that debate exposure led to increased cognitive and political involvement and EU support among young citizens. Unfortunately, the debate has only reached a very small audience

"BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with gdf9"

"Context: Bone morphogenetic protein (BMP)15 is an oocyte-specific growth factor, which, together with growth differentiation factor (GDF) 9, regulates folliculogenesis and ovulation rate. Multiple mutations in BMP15 have been identified in women with primary ovarian insufficiency (POI), supporting a pathogenic role; however, the underlying biological mechanism of many of these mutants remains unresolved. Objectives: To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15. Design: The effects of 10 mutations in BMP15 on protein production, activation of granulosa cells, and synergy with GDF9 were assessed. Results: Sequencing of 35 patients with POI identified both an unrecognized BMP15 variant (c.986G.A, R329H) and a variant (c.581T.C, F194S) previously associated with the condition. Assessing expression and activity of these and 8 other BMP15 mutants identified: (1) multiple variants, including L148P, F194S, and Y235C, with reduced mature protein production; (2) three variants (R138H, A180T, and R329H) with ;fourfold lower activity than wild-type BMP15; and (3) 3 variants (R68W, F194S, and N196K) with a significantly reduced ability to synergize with GDF9. Conclusions: Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likelyunderlie the physiologyofBMP15in thehumanovary. Copyright © 2017 by the Endocrine Society.